Process for producing erythromycin a derivative

ABSTRACT

An efficient process for producing an 11,12-cyclic carbamate 6-O-substituted ketolide derivatives having the natural stereochemistry at the 10-position.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a process for producing erythromycin Aderivatives and, more particularly, to a process for producingerythromycin A 11,12-cyclic carbamate 6-O-substituted ketolidederivatives.

2. Description of the Related Art

Erythromycin is an excellent antibacterial agent and has been widelyused clinically since the 1950's, but it is unstable to acids. In orderto overcome this drawback of erythromycin, a large number oferythromycin derivatives have been synthesized, and some of thesederivatives are clinically used as excellent antibiotics. For example,clarithromycin (6-O-methylerythromycin A, U.S. Pat. No. 4,331,803) iswidely used as a therapeutic agent of respiratory infections due to itsexcellent biological properties. There have been recently reported thederivatives which are generically called ketolides, and have potentantibacterial activity against macrolide-resistant bacteria (Bioorganicand Medicinal Chemistry Letters, Vol. 9, 3075-3080 (1999), Journal ofMedicinal Chemistry, Vol. 43, 1045-1049 (2000), Journal of Antibiotics,Vol. 54, 664-678 (2001)).

These ketolides are structurally characterized in that the cladinose atthe 3-position of erythromycin A is removed and converted into acarbonyl group, the 6-hydroxyl group is alkylated, and the11,12-hydroxyl groups are converted into a cyclic carbamate. It has everbeen reported that by reacting a 10,11-anhydro-12-O-imidazolyl carbonylderivative, in which the 3-position of erythromycin A has been convertedinto a carbonyl group, with liquid ammonia or aqueous ammonia so as tocarry out 11,12-cyclic carbamate formation, the natural R configurationand the unnatural S configuration with respect to the stereochemistry atthe 10-position are obtained as a mixture (Journal of MedicinalChemistry, Vol. 41, 4080-4100 (1998), Journal of Medicinal Chemistry,Vol. 43, 1045-1049 (2000)). It is therefore necessary to carry outcyclic carbamate formation of the 11,12-hydroxyl groups before chemicalmodification at the 3-position in order to produce a ketolide in highyield. This imposes restrictions on the order of the chemicalmodifications in the production of the ketolide, resulting in a long andrestricted production process.

SUMMARY OF THE INVENTION

An object of the present invention is to provide a selective andefficient process for producing erythromycin A 11,12-cyclic carbamatederivatives.

As a result of an intensive investigation, the present inventors havefound a process for leading to an 11,12-cyclic carbamate 6-O-substitutedketolide derivative having the natural stereochemistry at the10-position can be obtained selectively and efficiently by subjecting a10,11-anhydro-12-O-aminocarbonyl derivative, which has been derived froman 11,12-cyclic carbonate derivative of erythromycin A with the3-position thereof converted into a carbonyl group, to 11,12-cycliccarbamate formation with a specific type of base in combination with animidazole derivative or an alcohol, thereby the present invention hasbeen accomplished.

In further detail, the process is useful for production of3-deoxy-3-oxo-6-O-(3-(3-quinolyl)-2-propen-1-yl)-5-O-desosaminylerythronolideA 11,12-cyclic carbamate, which has been reported to have very strongantibacterial activity. In this process,3-deoxy-3-oxo-6-O-(3-(3-quinolyl)-2-propen-1-yl)-5-O-desosaminylerythronolideA 11,12-cyclic carbonate, which is described in U.S. Pat. No. 5,866,549,is used as a starting material; it is converted by a standard methodinto a compound in which the 2′-hydroxyl group is protected, a10,11-anhydro derivative (III) is derived from the 11,12-cycliccarbonate structure using a base such as triethylamine,1,8-diazabicyclo[5,4,0]undec-7-ene, potassium carbonate, sodiumcarbonate, barium carbonate, lithium carbonate, sodium hydroxide,potassium hydroxide, lithium hydroxide, barium hydroxide, or sodiumhydride, a 12-hydroxyl group is then activated using an activating agentsuch as N,N′-carbonyldiimidazole, phosgene, phosgene dimer, triphosgene,or ethyl chloroformate and then reacted with liquid ammonia, ammoniagas, or aqueous ammonia to give a 12-O-aminocarbonyl derivative (IV),and the compound (IV) is further converted into the 11,12-cycliccarbamate structure having the natural stereochemistry at the10-position using a base such as 1,8-diazabicyclo[5,4,0]undec-7-ene,sodium hydroxide, potassium hydroxide, lithium hydroxide, lithiumhydroxide hydrate, barium hydroxide, barium hydroxide hydrate, or sodiumhydride, and an imidazole derivative (imidazole or methylimidazole) oran alcohol (methanol, ethanol, or isopropanol).

That is, the present invention is the process for producing compound (V)defined below, which comprises the steps of:

(A) protecting the 2′-hydroxyl group of a compound (I) represented bythe formula below, which is used as a starting material,

(wherein R2 represents an alkyl group having 1 to 4 carbon atoms, allylgroup, and an allyl group substituted with an aromatic or hetero ringhaving 5 to 12 carbon atoms) with an R1 group (R1 represents acetylgroup, benzoyl group, propionyl group, trimethylsilyl group,triethylsilyl group, and t-butyldimethylsilyl group) to give a compound(II) represented by the formula below

(wherein R1 and R2 denote the same as above);

(B) treating the compound (II) with a base to give a compound (III)represented by the formula below

(wherein R1 and R2 denote the same as above);

(C) activating the 12-hydroxyl group of the compound (III) using anactivating agent, and then reacting with a compound represented byformula R3-NH₂ (wherein R3 represents hydrogen atom, amino group, analkyl group having 1 to 4 carbon atoms, and an alkyl group having 1 to 4carbon atoms that is substituted with a group selected from pyridylgroup, quinolyl group, imidazolyl group, and pyridylimidazolyl group) togive a compound (IV) represented by the formula below

(wherein R1, R2, and R3 denote the same as above); and

(D) subjecting the compound (IV) to cyclic carbamate formation using oneor more types of compound selected from the group consisting of1,8-diazabicyclo[5,4,0]undec-7-ene, cesium carbonate, lithium hydroxide,lithium hydroxide hydrate, potassium hydroxide, sodium hydroxide, bariumhydroxide, barium hydroxide hydrate, and sodium hydride in combinationwith one or more types of compound selected from the group consisting ofimidazole, methylimidazole, methanol, ethanol, and isopropanol to give acompound (V) represented by a formula below

(wherein R1, R2, and R3 denote the same as above).

The alkyl group having 1 to 4 carbon atoms referred to in the presentinvention includes a linear or branched alkyl group, and examplesthereof include methyl group, ethyl group, propyl group, isopropylgroup, butyl group, and t-butyl group. The base includes triethylamine,1,8-diazabicyclo[5,4,0]undec-7-ene, potassium carbonate, sodiumcarbonate, barium carbonate, lithium carbonate, sodium hydroxide,potassium hydroxide, lithium hydroxide, lithium hydroxide hydrate,barium hydroxide, barium hydroxide hydrate, and sodium hydride. Theactivating agent includes N,N′-carbonyldiimidazole, phosgene, phosgenedimer, triphosgene, and ethyl chloroformate. The compound represented byformula R3-NH₂ includes ammonia, hydrazine, an alkylamine having 1 to 4carbon atoms, and an alkylamine having 1 to 4 carbon atoms that issubstituted with a group selected from the group consisting of pyridylgroup, quinolyl group, imidazolyl group, and pyridylimidazolyl group.The alkylamine having 1 to 4 carbon atoms includes methylamine,ethylamine, propylamine, butylamine, and isopropylamine.

The present invention relates to a production process illustrated in thereaction scheme below. It relates to a process for producing compound(V) using compound (I) as a starting material, which is described inU.S. Pat. No. 5,866,549.

(wherein R1, R2, and R3 denote the same as above.)

Step 1: Compound (I), which is described in U.S. Pat. No. 5,866,549, isused as a starting material, and the 2′-hydroxyl group thereof isprotected with an R1 group (R1 denotes the same as above) by a standardmethod to give a compound (II).

Step 2: The compound (II) is treated with a base in an inert solvent ata temperature from 0° C. to the boiling temperature of the solvent, andpreferably at a temperature from room temperature to the boilingtemperature of the solvent, to give a compound (III). The inert solventavailable includes toluene, tetrahydrofuran, acetone, ethyl acetate,isopropyl acetate, methylene chloride, and the base available includestriethylamine, 1,8-diazabicyclo[5,4,0]undec-7-ene, potassium carbonate,sodium carbonate, barium carbonate, lithium carbonate, sodium hydroxide,potassium hydroxide, lithium hydroxide, barium hydroxide, sodiumhydride.

Step 3: The 12-hydroxyl group of the compound (III) obtained in Step 2is activated with an activating agent in an inert solvent at atemperature between −10° C. and 60° C., and preferably 0° C. to roomtemperature, and then reacted at the same reaction temperature with acompound represented by the formula R3-NH₂ (whrein R3 denotes the sameas above) to give a compound (IV). The inert solvent referred to here isthe same as that used in Step 2, and the activating agent availableincludes N,N′-carbonyldiimidazole, phosgene, phosgene dimer,triphosgene, ethyl chloroformate. The compound represented by theformula R3-NH₂ includes ammonia, hydrazine, an alkylamine having 1 to 4carbon atoms, and an alkylamine having 1 to 4 carbon atoms that issubstituted with a group selected from pyridyl group, quinolyl group,imidazolyl group, pyridylimidazolyl group, preferably ammonia,hydrazine, and an alkylamine having 1 to 4 carbon atoms.

Step 4: The compound (IV) obtained in Step 3 is subjected to cycliccarbamate formation in an inert solvent at a temperature between −10° C.and 60° C., and preferably 0° C. to room temperature, using a specifictype of base in combination with an imidazole derivative or an alcoholto give the target compound (V). The inert solvent referred to here isthe same as that used in Step 2; the base available includes one or moretypes selected from 1,8-diazabicyclo[5,4,0]undec-7-ene, cesiumcarbonate, lithium hydroxide, lithium hydroxide hydrate, potassiumhydroxide, sodium hydroxide, barium hydroxide, barium hydroxide hydrate,and sodium hydride. The imidazole derivative available includesimidazole and methylimidazole. The alcohol available includes methanol,ethanol, and isopropanol. The imidazole derivative and the alcohol maybe used singly or in a combination of two or more types. By making thealcohol serve also as the solvent, 11,12-cyclic carbamate formation andremoval of the protecting group at the 2′-position can be carried out atthe same time, and the 2′-hydroxyl derivatives and the 2′-protectedderivatives can be selectively produced freely as required.

PREFERRED EMBODIMENT OF THE INVENTION

The present invention is explained below in further detail.

EXAMPLE 1 Production of10,11-anhydro-2′-O-benzoyl-3,11-dideoxy-3-oxo-6-O-(3-(3-quinolyl)-2-propen-1-yl)-5-O-desosaminylerythronolideA

A compound (20.0 g) obtained by subjecting3-deoxy-3-oxo-6-O-(3-(3-quinolyl)-2-propen-1-yl)-5-O-desosaminylerythronolideA 11,12-cyclic carbonate, which is described in Example 75 of U.S. Pat.No. 5,866,549, to 2′-O-benzoylation by a standard method was dissolvedin tetrahydrofuran (400 mL), anhydrous potassium carbonate (15.9 g, 5equivalents) was added thereto, and the mixture was heated and refluxedfor 23 hours. After allowing it to cool, a precipitate was filtered off(washed with ethyl acetate (200 mL)), the filtrate thus obtained waswashed with saturated brine, dried with anhydrous magnesium sulfate, andfiltered, and the solvent was distilled off under vacuum. The crudeproduct thus obtained was subjected to purification by silica gel columnchromatography (eluent acetone:hexane:triethylamine=3:10:0.2 to5:10:0.2) to give the title compound (19.8 g).

¹H NMR(500 MHz, CDCl₃) δ (ppm): 2.03(s, 3H, 10-Me), 4.97(dd, 1H, J=10.3,2.6 Hz, 13-H), 5.07(dd, 1H, J=10.4, 7.6 Hz, 2′-H), 6.48(s, 1H, 11-H),8.89(d, 1H, J=2.1 Hz, 2-H of quinoline)

¹³C NMR(125 MHz, CDCl₃) δ (ppm): 73.5(12-C), 139.8(10-C), 141.1(11-C),208.3(3-C & 9-C)

ESI-MS: m/z=849.2[M+Na]⁺

EXAMPLE 2 Production of10,11-anhydro-12-O-aminocarbonyl-2′-O-benzoyl-3,11-dideoxy-3-oxo-6-O-(3-(3-quinolyl)-2-propen-1-yl)-5-O-desosaminylerythronolideA

The compound (18.6 g) obtained in Example 1 was dissolved intetrahydrofuran (372 mL), carbonyldiimidazole (10.9 g, 3 equivalents)and 1,8-diazabicyclo[5,4,0]undec-7-ene (342 mg, 0.1 equivalents) wereadded thereto, and the mixture was stirred for 3 hours while cooling.Subsequently, ammonia gas was passed through the mixture for 18.5 hourswhile ice cooling. Toluene (400 mL) and saturated brine (100 mL) wereadded to the mixture at room temperature and separated, the organicphase thus obtained was washed twice with saturated brine (100 mL),dried with anhydrous magnesium sulfate, and filtered, and the solventwas then distilled off under vacuum to give the title compound (20.2 g).

¹H NMR(500 MHz, CDCl₃) δ (ppm): 1.90(s, 3H, 10-Me), 5.82(m, 1H, 13-H),6.75(s, 1H, 11-H)

¹³C NMR(125 MHz, CDCl₃) δ (ppm): 138.3(10-C), 141.1(11-C),154.4(12-O—CO—NH₂)

ESI-MS: m/z=870.3[M+H]⁺

EXAMPLE 3 Production of2′-O-benzoyl-3-deoxy-3-oxo-6-O-(3-(3-quinolyl)-2-propen-1-yl)-5-O-desosaminylerythronolideA 11,12-cyclic carbamate

The compound (15.0 g) obtained in Example 2 was dissolved in toluene(500 mL), and the solvent was then distilled off under vacuum. Theresidue thus obtained was dissolved in anhydrous toluene (150 mL),imidazole (2.35 g, 2 equivalents) and cesium carbonate (5.62 g, 1equivalent) were added thereto, and the mixture was stirred at roomtemperature for 3.5 hours. Saturated aqueous ammonium chloride (250 mL)was added to the reaction mixture, the mixture was separated, and then,the aqueous phase was extracted twice with toluene (50 mL). The combinedorganic phases were washed three times with saturated aqueous ammoniumchloride (50 mL), washed with saturated brine (50 mL), dried withanhydrous magnesium sulfate, and filtered, and the solvent was distilledoff under vacuum to give the title compound (14.0 g, yield 93.3%).

¹H NMR(500 MHz, CDCl₃) δ (ppm): 2.26(s, 6H, NMe₂), 2.88(m, 1H, 10-H),3.86(s, 1H, 11-H), 5.49(s, 1H, NH)

¹³C NMR(125 MHz, CDCl₃) δ (ppm): 37.2(10-C), 58.1(11-C), 83.4(12-C),157.6(12-O—CO-1-11)

ESI-MS: m/z=892.4[M+Na]⁺

EXAMPLE 4

The compound (500 mg) obtained in Example 2 was subjected to a reactionin the same manner as in Example 3 using cesium carbonate (56 mg, 0.3equivalents) and imidazole (19.5 mg, 0.5 equivalents) in anhydroustoluene (5 mL) to give the same compound (479 mg, yield 95.8%) as thatobtained in Example 3.

EXAMPLE 5

The compound (500 mg) obtained in Example 2 was subjected to a reactionin the same manner as in Example 3 using cesium carbonate (188 mg, 1equivalent) and methanol (37 mg, 2 equivalents) in anhydrous toluene (5mL) to give the same compound (481 mg, yield 96.2%) as that obtained inExample 3.

EXAMPLE 6

The compound (500 mg) obtained in Example 2 was subjected to a reactionin the same manner as in Example 3 using potassium hydroxide (38 mg, 1equivalent) and imidazole (78 mg, 2 equivalents) in anhydrous toluene (5mL) to give the same compound (425 mg, yield 85.0%) as that obtained inExample 3.

EXAMPLE 7

The compound (500 mg) obtained in Example 2 was subjected to a reactionin the same manner as in Example 3 using anhydrous lithium hydroxide (14mg, 1 equivalent) and imidazole (78 mg, 2 equivalents) in anhydroustoluene (5 mL) to give the same compound (464 mg, yield 92.8%) as thatobtained in Example 3.

EXAMPLE 8

The compound (500 mg) obtained in Example 2 was subjected to a reactionin the same manner as in Example 3 using1,8-diazabicyclo[5,4,0]undec-7-ene (87.5 mg, 1 equivalent) and imidazole(78 mg, 2 equivalents) in anhydrous toluene (5 mL) to give the samecompound (481 mg, yield 96.2%) as that obtained in Example 3.

EXAMPLE 9 Production of3-deoxy-3-oxo-6-O-(3-(3-quinolyl)-2-propen-1-yl)-5-O-desosaminylerythronolideA 11,12-cyclic carbamate (compound described in Example 104 of U.S. Pat.No. 5,866,549)

3-Deoxy-3-oxo-6-O-(3-(3-quinolyl)-2-propen-1-yl)-5-O-desosaminylerythronolideA 11,12-cyclic carbonate, which is described in Example 75 of U.S. Pat.No. 5,866,549, was subjected to 2′-O-acetylation by a standard methodand then to reactions in the same manner as in Examples 1 and 2 to givea compound (501 mg) to which was added1,8-diazabicyclo[5,4,0]undec-7-ene (9 mg, 0.1 equivalents), and themixture was stirred in methanol (10 mL) at room temperature for 44hours. The solvent was distilled off under vacuum, to the residue thusobtained was added toluene (100 mL), and it was washed twice withsaturated brine (10 mL). The washings were subjected to extraction usingethyl acetate (10 mL), the combined organic phases were dried withanhydrous magnesium sulfate and filtered, and the solvent was distilledoff under vacuum. The residue thus obtained was subjected topurification by silica gel column chromatography to give the titlecompound (379 mg, yield 79.8%).

EXAMPLES 10-13

The compound obtained in Example 2 was reacted in anhydrous tolueneunder the conditions shown in Table 1 to give the same compound as thatobtained in Example 3 in the yields shown in the table. TABLE 1 Tem-HPLC Example Reagent perature Time (Pa %:254 nm) 10 Sodium hydride 1eqr.t.  5 h 80.1 Imidazole 2eq 11 Sodium hydroxide 1eq r.t.  5 h 81.6Imidazole 2eq 12 Lithium hydroxide 1eq r.t. 13 h 85.3 monohydrateImidazole 2eq 13 Barium hydroxide 1eq r.t. 18 h 86.6 octahydrateImidazole 2eq

1. A process for producing a compound (V) comprising: (A) protecting the2′-hydroxyl group of a compound (I) represented by a formula below,which is used as a starting material,

(wherein R2 represents an alkyl group having 1 to 4 carbon atoms, allylgroup, and an allyl group substituted with an aromatic or hetero ringhaving 5 to 12 carbon atoms) with an R1 group (R1 represents acetylgroup, benzoyl group, propionyl group, trimethylsilyl group,triethylsilyl group, and t-butyldimethylsilyl group) to give a compound(II) represented by a formula below

(wherein R1 and R2 denote the same as above); (B) treating said compound(II) with a base to give a compound (III) represented by a formula below

(wherein R1 and R2 denote the same as above); (C) activating the12-hydroxyl group of said compound (III) using an activating agent, andthen reacting with a compound represented by formula R3-NH₂ (wherein R3represents hydrogen atom, amino group, an alkyl group having 1 to 4carbon atoms, and an alkyl group having 1 to 4 carbon atoms that issubstituted with a group selected from pyridyl group, quinolyl group,imidazolyl group, and pyridylimidazolyl group) to give a compound (IV)represented by a formula below

(wherein R1, R2, and R3 denote the same as above); and (D) subjectingsaid compound (IV) to cyclic carbamate formation using one or more typesof compound selected from a group consisting of1,8-diazabicyclo[5,4,0]undec-7-ene, cesium carbonate, lithium hydroxide,lithium hydroxide hydrate, potassium hydroxide, sodium hydroxide, bariumhydroxide, barium hydroxide hydrate, and sodium hydride in combinationwith one or more types of compound selected from a group consisting ofimidazole, methylimidazole, methanol, ethanol, and isopropanol to givesaid compound (V) represented by a formula below

(wherein R1, R2, and R3 denote the same as above).